Cadenas.E. – Handbook of ...

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Handbook
of
Antioxidants
Revised and Expanded
edited by
Enrique Cadenas
Lester Packer
University of Southern California School of Pharmacy
Los Angeles, California
MARCEL DEKKER, INC.
NEW YORK
•
BASEL
TM
Second Edition
ISBN: 0-8247-0547-5
This book is printed on acid-free paper.
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mation, write to Special Sales/Professional Marketing at the headquarters address above.
Copyright © 2002 by Marcel Dekker, Inc. All Rights Reserved.
Neither this book nor any part may be reproduced or transmitted in any form or by any
means, electronic or mechanical, including photocopying, microfilming, and recording, or by
any information storage and retrieval system, without permission in writing from the publisher.
Current printing (last digit):
10987654321
PRINTED IN THE UNITED STATES OF AMERICA
Copyright © 2002 by Taylor & Francis Group, LLC
 OXIDATIVE STRESS AND DISEASE
Series Editors
L
ESTER
P
ACKER
, P
H
.D.
E
NRIQUE
C
ADENAS
, M.D., P
H
.D.
University of Southern California School of Pharmacy
Los Angeles, California
Olivier, and Catherine Pasquier
2.
Understanding the Process of Aging: The Roles of Mitochondria, Free Radicals,
and Antioxidants,
edited by Enrique Cadenas and Lester Packer
3. Redox Regulation of Cell Signaling and Its Clinical Application,
edited by Lester
Packer and Junji Yodoi
4. Antioxidants in Diabetes Management,
edited by Lester Packer, Peter R
é
ö
sen,
Hans J. Tritschler, George L. King, and Angelo Azzi
5. Free Radicals in Brain Pathophysiology,
edited by Giuseppe Poli, Enrique
Cadenas, and Lester Packer
6. Nutraceuticals in Health and Disease Prevention,
edited by Klaus Kr
ä
mer,
Peter-Paul Hoppe, and Lester Packer
7. Environmental Stressors in Health and Disease,
edited by J
ü
rgen Fuchs and
Lester Packer
8. Handbook of Antioxidants: Second Edition, Revised and Expanded,
edited by
Enrique Cadenas and Lester Packer
Related Volumes
Vitamin E in Health and Disease: Biochemistry and Clinical Applications,
edited
by Lester Packer and J
ü
rgen Fuchs
Vitamin A in Health and Disease,
edited by Rune Blomhoff
Free Radicals and Oxidation Phenomena in Biological Systems,
edited by
Marcel Roberfroid and Pedro Buc Calderon
Biothiols in Health and Disease,
edited by Lester Packer and Enrique Cadenas
Handbook of Antioxidants,
edited by Enrique Cadenas and Lester Packer
Handbook of Synthetic Antioxidants,
edited by Lester Packer and Enrique
Cadenas
Vitamin C in Health and Disease,
edited by Lester Packer and J
ü
rgen Fuchs
Lipoic Acid in Health and Disease,
edited by J
ü
rgen Fuchs, Lester Packer, and
Guido Zimmer
Flavonoids in Health and Disease,
edited by Catherine Rice-Evans and Lester
Packer
Additional Volumes in Preparation
1. Oxidative Stress in Cancer, AIDS, and Neurodegenerative Diseases,
edited by
Luc Montagnier, Ren
Series Introduction
Oxygen is a dangerous friend. Overwhelming evidence indicates that oxidative stress can lead
to cell and tissue injury. However, the same free radicals that are generated during oxidative
stress are produced during normal metabolism and thus are involved in both human health and
disease.
Free radicals are molecules with an odd number of electrons. The odd, or unpaired, electron
is highly reactive as it seeks to pair with another free electron.
Free radicals are generated during oxidative metabolism and energy production in the body.
Free radicals are involved in:
Enzyme-catalyzed reactions
Electron transport in mitochondria
Signal transduction and gene expression
Activation of nuclear transcription factors
Oxidative damage to molecules, cells, and tissues
Antimicrobial action of neutrophils and macrophages
Aging and disease
Normal metabolism is dependent on oxygen, a free radical. Through evolution, oxygen
was chosen as the terminal electron acceptor for respiration. The two unpaired electrons of
oxygen spin in the same direction; thus, oxygen is a biradical, but not a very dangerous free
radical. Other oxygen-derived free radical species, such as superoxide or hydroxyl radicals,
formed during metabolism or by ionizing radiation are stronger oxidants and are therefore
more dangerous.
In addition to research on the biological effects of these reactive oxygen species, research
on reactive nitrogen species has been gathering momentum. NO, or nitrogen monoxide (nitric
oxide), is a free radical generated by NO synthase (NOS). This enzyme modulates physiolog-
ical responses such as vasodilation or signaling in the brain. However, during inflammation,
synthesis of NOS (iNOS) is induced. This iNOS can result in the overproduction of NO, caus-
ing damage. More worrisome, however, is the fact that excess NO can react with superoxide
to produce the very toxic product peroxynitrite. Oxidation of lipids, proteins, and DNA can
result, thereby increasing the likelihood of tissue injury.
Copyright © 2002 by Taylor & Francis Group, LLC
 Both reactive oxygen and nitrogen species are involved in normal cell regulation, in which
oxidants and redox status are important in signal transduction. Oxidative stress is increasingly
seen as a major upstream component in the signaling cascade involved in inflammatory re-
sponses, stimulating adhesion molecule and chemoattractant production. Hydrogen peroxide,
which breaks down to produce hydroxyl radicals, can also activate NF-
κ
B, a transcription fac-
tor involved in stimulating inflammatory responses. Excess production of these reactive species
is toxic, exerting cytostatic effects, causing membrane damage, and activating pathways of cell
death (apoptosis and/or necrosis).
Virtually all diseases thus far examined involve free radicals. In most cases, free radicals
are secondary to the disease process, but in some instances free radicals are causal. Thus, there
is a delicate balance between oxidants and antioxidants in health and disease. Their proper
balance is essential for ensuring healthy aging.
The term oxidative stress indicates that the antioxidant status of cells and tissues is altered
by exposure to oxidants. The redox status is thus dependent on the degree to which a cell’s
components are in the oxidized state. In general, the reducing environment inside cells helps to
prevent oxidative damage. In this reducing environment, disulfide bonds (S—S) do not sponta-
neously form because sulfhydryl groups kept in the reduced state (SH) prevent protein misfold-
ing or aggregation. This reducing environment is maintained by oxidative metabolism and by
the action of antioxidant enzymes and substances, such as glutathione, thioredoxin, vitamins E
and C, and enzymes such as superoxide dismutase (SOD), catalase, and the selenium-dependent
glutathione and thioredoxin hydroperoxidases, which serve to remove reactive oxygen species.
Changes in the redox status and depletion of antioxidants occur during oxidative stress. The
thiol redox status is a useful index of oxidative stress mainly because metabolism and NADPH-
dependent enzymes maintain cell glutathione (GSH) almost completely in its reduced state.
Oxidized glutathione (glutathione disulfide, GSSG) accumulates under conditions of oxidant
exposure, and this changes the ratio of oxidized to reduced glutathione; an increased ratio
indicates oxidative stress. Many tissues contain large amounts of glutathione, 2–4 mM in
erythrocytes or neural tissues and up to 8 mM in hepatic tissues. Reactive oxygen and nitrogen
species can directly react with glutathione to lower the levels of this substance, the cell’s
primary preventative antioxidant.
Current hypotheses favor the idea that lowering oxidative stress can have a clinical benefit.
Free radicals can be overproduced or the natural antioxidant system defenses weakened, first
resulting in oxidative stress, and then leading to oxidative injury and disease. Examples of
this process include heart disease and cancer. Oxidation of human low-density lipoproteins is
considered the first step in the progression and eventual development of atherosclerosis, leading
to cardiovascular disease. Oxidative DNA damage initiates carcinogenesis.
Compelling support for the involvement of free radicals in disease development comes
from epidemiological studies showing that an enhanced antioxidant status is associated with
reduced risk of several diseases. Vitamin E and prevention of cardiovascular disease is a notable
example. Elevated antioxidant status is also associated with decreased incidence of cataracts
and cancer, and some recent reports have suggested an inverse correlation between antioxidant
status and occurrence of rheumatoid arthritis and diabetes mellitus. Indeed, the number of
indications in which antioxidants may be useful in the prevention and/or the treatment of
disease is increasing.
Oxidative stress, rather than being the primary cause of disease, is more often a secondary
complication in many disorders. Oxidative stress diseases include inflammatory bowel diseases,
retinal ischemia, cardiovascular disease and restenosis, AIDS, ARDS, and neurodegenerative
diseases such as stroke, Parkinson’s disease, and Alzheimer’s disease. Such indications may
Copyright © 2002 by Taylor & Francis Group, LLC
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